A unique glucose-dependent apoptotic pathway induced by c-Myc.
The lactate dehydrogenase A (LDH-A) gene, whose product participates in normal anaerobic glycolysis and is frequently increased in human cancers, has been identified as a c-Myc-responsive gene. It was of interest, therefore, to compare the effect of glucose deprivation in c-Myc-transformed and nontransformed cells. We observed that glucose deprivation or treatment with the glucose antimetabolite 2-deoxyglucose caused nontransformed cells to arrest in the G0/G1 phase of the cell cycle. In contrast, c-Myc-transformed fibroblasts, lymphoblastoid, or lung carcinoma cells underwent extensive apoptosis. Ectopic expression of LDH-A alone in Rat1a fibroblasts was sufficient to induce apoptosis with glucose deprivation but not with serum withdrawal, suggesting that LDH-A mediates the unique apoptotic effect of c-Myc when glycolysis is blocked. The apoptosis caused by glucose deprivation was blocked by Bcl-2 expression but appeared to be independent of wild-type p53 activity. These studies provide insights on the coupling of glucose metabolism and the cell cycle in c-Myc-transformed cells and may in the future be exploited for cancer therapeutics.
Shim
H
H
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Chun
Y S
YS
Lewis
B C
BC
Dang
C V
CV
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D016259:Genes, myc; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000502:physiology*; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051381:Rats; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D003847:Deoxyglucose; D007770:L-Lactate Dehydrogenase; D005947:Glucose